Sphingosine-1-phosphate (SPP) is an intracellular second messenger regulating cell survival, growth, motility, and differentiation acting through effects on calcium mobilization, cytoskeleton reorganization, and initiation of second messenger cascades. SPP has also been shown to be the ligand for the EDG-1 family of G protein-coupled receptors, which includes EDG-1, -3, -5, and most recently, EDG-8. As with other members of the EDG-1 family, EDG-8 binds SPP with high affinity and remarkable specificity. The biological functions of EDG-l receptors are not well understood. EDG-8, initially cloned by Dr. Norman Lee as a nerve growth factor receptor in rat pheochromocytoma (PC12) cells, is preferentially expressed in the brain. It may also be a cell surface receptor responsible for somite rounding and neurite retraction. In fact, the binding of SPP to EDG-8 may modulate neuritogenesis, a key event in both neuronal development and plasticity following injury or disease. The substantiation of EDG-8/SPP induced neurite retraction using stable and transiently transfected PC12 cells, followed by the examination of cAMP accumulation, MAPK family member activation, and small G protein activation will permit the determination of the involved molecular mechanisms. Further studies with specific inhibitors, as well as dominant-negative, knock-out, and antisense mutants will be used for this purpose. SPP might play a role during normal brain development or after traumatic injury by acting through EDG-8 to affect neuritogenesis. The elucidation of the relevant signaling pathways in SPP/EDG-8 induced neurite retraction and cell rounding might provide clues for the development of agents that can affect the process of neuritogenesis. Such agents might be useful as potential treatments for developmental disorders as well as the neurodegeneration in Alzheimer's disease, Pick's disease, ischemia, and traumatic injury.